tbuckley/cabot-search huggingface dataset:
Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli‐Responsive Nanocages
Authors: María Sancho‐Albero, Giorgio Facchetti, Nicolò Panini, Marina Meroni, Ezia Bello, Isabella Rimoldi, Massimo Zucchetti, Roberta Frapolli, Luisa De Cola
Journal: Advanced Healthcare Materials (2023)

Abstract Platinum‐based chemotherapy is the first‐line treatment for different cancer types, and in particular, for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinum IV (Pt IV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl 2 (OH) 2 ), (dach = R , R ‐diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt‐based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient‐derived malignant pleural mesothelioma. MPM487 confirms the well‐known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the Pt IV , entrapped in the nanocages, at an equivalent dose of the platinum complex.
Transcriptional and Clonal Characterization of Cytotoxic T Cells in Crescentic Glomerulonephritis
Authors: Anne Mueller, Yu Zhao, Hakan Cicek, Hans-Joachim Paust, Amirrtavarshni Sivayoganathan, Alexandra Linke, Claudia Wegscheid, Thorsten Wiech, Tobias B. Huber, Catherine Meyer-Schwesinger, Stefan Bonn, Immo Prinz, Ulf Panzer, Gisa Tiegs, Christian F. Krebs, Katrin Neumann
Journal: Journal of the American Society of Nephrology (2023)

T-cell infiltration is a hallmark of crescentic GN (cGN), often caused by ANCA-associated vasculitis. Pathogenic T-cell subsets, their clonality, and downstream effector mechanisms leading to kidney injury remain to be fully elucidated. Single-cell RNA sequencing and T-cell receptor sequencing revealed activated, clonally expanded cytotoxic CD4 + and CD8 + T cells in kidneys from patients with ANCA-associated cGN. In experimental cGN, kidney-infiltrating CD8 + T cells expressed the cytotoxic molecule, granzyme B (GzmB), which induced apoptosis in renal tissue cells by activation of procaspase-3, and aggravated disease pathology. These findings describe a pathogenic function of (clonally expanded) cytotoxic T cells in cGN and identify GzmB as a mediator and potential therapeutic target in immune-mediated kidney disease.
Alleviating the unwanted effects of oxidative stress on Aβ clearance: a review of related concepts and strategies for the development of computational modelling
Authors: Sarawoot Somin, Don Kulasiri, Sandhya Samarasinghe
Journal: Translational Neurodegeneration (2023)

Abstract Treatment for Alzheimer’s disease (AD) can be more effective in the early stages. Although we do not completely understand the aetiology of the early stages of AD, potential pathological factors (amyloid beta [Aβ] and tau) and other co-factors have been identified as causes of AD, which may indicate some of the mechanism at work in the early stages of AD. Today, one of the primary techniques used to help delay or prevent AD in the early stages involves alleviating the unwanted effects of oxidative stress on Aβ clearance. 4-Hydroxynonenal (HNE), a product of lipid peroxidation caused by oxidative stress, plays a key role in the adduction of the degrading proteases. This HNE employs a mechanism which decreases catalytic activity. This process ultimately impairs Aβ clearance. The degradation of HNE-modified proteins helps to alleviate the unwanted effects of oxidative stress. Having a clear understanding of the mechanisms associated with the degradation of the HNE-modified proteins is essential for the development of strategies and for alleviating the unwanted effects of oxidative stress. The strategies which could be employed to decrease the effects of oxidative stress include enhancing antioxidant activity, as well as the use of nanozymes and/or specific inhibitors. One area which shows promise in reducing oxidative stress is protein design. However, more research is needed to improve the effectiveness and accuracy of this technique. This paper discusses the interplay of potential pathological factors and AD. In particular, it focuses on the effect of oxidative stress on the expression of the Aβ-degrading proteases through adduction of the degrading proteases caused by HNE. The paper also elucidates other strategies that can be used to alleviate the unwanted effects of oxidative stress on Aβ clearance. To improve the effectiveness and accuracy of protein design, we explain the application of quantum mechanical/molecular mechanical approach.
Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: A national population-based cohort study
Authors: Ines Lakbar, Marc Leone, Vanessa Pauly, Veronica Orleans, Kossi Josue Srougbo, Sambou Diao, Pierre-Michel Llorca, Marco Solmi, Christoph U. Correll, Sara Fernandes, Jean-Louis Vincent, Laurent Boyer, Guillaume Fond
Journal: PLoS Medicine (2023)

Background Patients with severe mental illness (SMI) (i.e., schizophrenia, bipolar disorder, or major depressive disorder) have been reported to have excess mortality rates from infection compared to patients without SMI, but whether SMI is associated with higher or lower case fatality rates (CFRs) among infected patients remains unclear. The primary objective was to compare the 90-day CFR in septic shock patients with and without SMI admitted to the intensive care unit (ICU), after adjusting for social disadvantage and physical health comorbidity. Methods and findings We conducted a nationwide, population-based cohort study of all adult patients with septic shock admitted to the ICU in France between January 1, 2014, and December 31, 2018, using the French national hospital database. We matched (within hospitals) in a ratio of 1:up to 4 patients with and without SMI (matched-controls) for age (5 years range), sex, degree of social deprivation, and year of hospitalization. Cox regression models were conducted with adjustment for smoking, alcohol and other substance addiction, overweight or obesity, Charlson comorbidity index, presence of trauma, surgical intervention, Simplified Acute Physiology Score II score, organ failures, source of hospital admission (home, transfer from other hospital ward), and the length of time between hospital admission and ICU admission. The primary outcome was 90-day CFR. Secondary outcomes were 30- and 365-day CFRs, and clinical profiles of patients. A total of 187,587 adult patients with septic shock admitted to the ICU were identified, including 3,812 with schizophrenia, 2,258 with bipolar disorder, and 5,246 with major depressive disorder. Compared to matched controls, the 90-day CFR was significantly lower in patients with schizophrenia (1,052/3,269 = 32.2% versus 5,000/10,894 = 45.5%; adjusted hazard ratio (aHR) = 0.70, 95% confidence interval (CI) 0.65,0.75, p &lt; 0.001), bipolar disorder (632/1,923 = 32.9% versus 2,854/6,303 = 45.3%; aHR = 0.70, 95% CI = 0.63,0.76, p &lt; 0.001), and major depressive disorder (1,834/4,432 = 41.4% versus 6,798/14,452 = 47.1%; aHR = 0.85, 95% CI = 0.81,0.90, p &lt; 0.001). Study limitations include inability to capture deaths occurring outside hospital, lack of data on processes of care, and problems associated with missing data and miscoding in medico-administrative databases. Conclusions Our findings suggest that, after adjusting for social disadvantage and physical health comorbidity, there are improved septic shock outcome in patients with SMI compared to patients without. This finding may be the result of different immunological profiles and exposures to psychotropic medications, which should be further explored.
Re-emergence of SARS-CoV-2 Omicron subvariant XBB.1.5: present status, treatment, and future outlook – 2023
Authors: Shopnil Akash, Md. Shajib Khan, Nobendu Mukerjee, Shabana Bibi
Journal: International Journal of Surgery (2023)

Akash, Shopnil MPharm; Khan, Md. Shajib MPharm; Mukerjee, Nobendu MSc; Bibi, Shabana PhD Author Information
Association Between Medicaid Waivers and Medicaid Disenrollment Among Autistic Adolescents During the Transition to Adulthood
Authors: Meghan E. Carey, Sha Tao, Kaitlin H. Koffer Miller, Steven C. Marcus, David S. Mandell, Andrew J. Epstein, Lindsay L. Shea
Journal: JAMA Network Open (2023)

This cohort study examines whether Medicaid waivers were associated with a reduced risk of Medicaid disenrollment among autistic adolescents who are transitioning to adulthood.
Testosterone Coordinates Gene Expression Across Different Tissues to Produce Carotenoid-Based Red Ornamentation
Authors: Sarah Khalil, Erik D Enbody, Carolina Frankl-Vilches, Joseph F Welklin, Rebecca E Koch, Matthew B Toomey, Simon Yung Wa Sin, Scott V Edwards, Manfred Gahr, Hubert Schwabl, Michael S Webster, Jordan Karubian
Journal: Molecular Biology and Evolution (2023)

Abstract Carotenoid pigments underlie most of the red, orange, and yellow visual signals used in mate choice in vertebrates. However, many of the underlying processes surrounding the production of carotenoid-based traits remain unclear due to the complex nature of carotenoid uptake, metabolism, and deposition across tissues. Here, we leverage the ability to experimentally induce the production of a carotenoid-based red plumage patch in the red-backed fairywren (Malurus melanocephalus), a songbird in which red plumage is an important male sexual signal. We experimentally elevated testosterone in unornamented males lacking red plumage to induce the production of ornamentation and compared gene expression in both the liver and feather follicles between unornamented control males, testosterone-implanted males, and naturally ornamented males. We show that testosterone upregulates the expression of CYP2J19, a gene known to be involved in ketocarotenoid metabolism, and a putative carotenoid processing gene (ELOVL6) in the liver, and also regulates the expression of putative carotenoid transporter genes in red feather follicles on the back, including ABCG1. In black feathers, carotenoid-related genes are downregulated and melanin genes upregulated, but we find that carotenoids are still present in the feathers. This may be due to the activity of the carotenoid-cleaving enzyme BCO2 in black feathers. Our study provides a first working model of a pathway for carotenoid-based trait production in free-living birds, implicates testosterone as a key regulator of carotenoid-associated gene expression, and suggests hormones may coordinate the many processes that underlie the production of these traits across multiple tissues.
Can prophylactic tamsulosin reduce the risk of urinary retention after surgery? A systematic review and meta-analysis of randomized control trials
Authors: Zhaohui Zhou, Wenyi Gan, Zhiyong Li, Zhen Li, Fangjian Zhou, Hua Li, Zhuowei Liu
Journal: International Journal of Surgery (2023)

Objective: The meta-analysis aimed to integrate the evidence of randomized control trials to estimate the efficacy of prophylactic tamsulosin on postoperative urinary retention (POUR). Methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were searched through 1 March 2022 using predetermined keywords. Randomized control trials reporting the preventive efficacy of prophylactic tamsulosin against POUR were identified according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guideline. Pooled risk ratios (RRs) were calculated using a random-effects model or a fixed-effects model based on the results of heterogeneity assessment. A meta-regression analysis was performed to explore the potential sources of heterogeneity. Results: There were 14 studies with 1102 patients in the Tamsulosin group and 1119 patients in the Control group. The risk of POUR was significantly lower in the Tamsulosin group (156/1102 [14.2%] vs. 238/1119 [21.3%]; RR=0.65; 95% CI: 0.50–0.86; P =0.002; Heterogeneity: I 2 =51%; P =0.01). Tamsulosin administration was associated with a higher risk of adverse events (65/614 [10.6%] vs. 39/626 [6.2%]; RR=1.72; 95% CI: 1.19–2.48; P =0.004; Heterogeneity: I 2 =0%; P =0.70). The meta-regression identified the mean age of patients as the only potential source of heterogeneity. Subgroup analysis showed that the younger patients (age &lt;50 years) might benefit more from tamsulosin intake (RR=0.36; 95% CI: 0.19–0.70; P =0.003; Heterogeneity: I 2 =49%; P =0.14). Conclusions: The current meta-analysis suggested that prophylactic tamsulosin contributed to the prevention of POUR, and younger patients (&lt;50 years) might benefit more from this preventive regimen. Tamsulosin was also associated with a higher risk of adverse events.
Variation in Early Anakinra Use and <scp>Short‐Term</scp> Outcomes in Multisystem Inflammatory Syndrome in Children
Authors: Joyce C. Chang, Cameron C. Young, Eyal Muscal, Sara K. Sexson Tejtel, Margaret M. Newhams, Suden Kucukak, Hillary Crandall, Aline B. Maddux, Courtney M. Rowan, Natasha B. Halasa, Helen A. Harvey, Charlotte V. Hobbs, Mark W. Hall, Michele Kong, Cassyanne L. Aguiar, Jennifer E. Schuster, Julie C. Fitzgerald, Aalok R. Singh, Kari Wellnitz, Ryan A. Nofziger, Natalie Z. Cvijanovich, Elizabeth H. Mack, Adam J. Schwarz, Sabrina M. Heidemann, Jane W. Newburger, Laura D. Zambrano, Angela P. Campbell, Manish M. Patel, Adrienne G. Randolph, Mary Beth F. Son
Journal: Arthritis & Rheumatology (2023)

Objective Evidence regarding effectiveness of interleukin‐1 receptor antagonism in multisystem inflammatory syndrome in children (MIS‐C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy. Methods We conducted a retrospective cohort study of MIS‐C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0–1) were identified. We compared cases in patients ages 2–20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days 0–1, using inverse probability weighting to balance disease severity. Primary outcomes were vasopressor requirement on day 3 and impaired left ventricular ejection fraction on days 3–4. The secondary outcome was 50% reduction in C‐reactive protein on day 3. Results Among 1,516 MIS‐C cases at 44 sites, 193 (13%) patients received anakinra alone or with other immunomodulators as initial treatment (range 0–74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing disease severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (n = 121) versus IVIG plus glucocorticoids (n = 389) was not associated with significant differences in vasopressor requirement (25.6% versus 20.1%, respectively; risk ratio [RR] 1.27 [95% confidence interval (95% CI) 0.88–1.84]), ventricular dysfunction (33.7% versus 25.7%, respectively; RR 1.31 [95% CI 0.98–1.75]), or C‐reactive protein reduction. Conclusion We identified substantial variation in initial anakinra use in a real‐world population of children with MIS‐C, but no average short‐term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone.
HExpPredict: <i>In Vivo</i> Exposure Prediction of Human Blood Exposome Using a Random Forest Model and Its Application in Chemical Risk Prioritization
Authors: Fanrong Zhao, Li Li, Penghui Lin, Yue Chen, Shipei Xing, Huili Du, Zheng Wang, Junjie Yang, Tao Huan, Cheng Long, Limao Zhang, Bin Wang, Mingliang Fang
Journal: Environmental Health Perspectives (2023)

Background: Due to many substances in the human exposome, there is a dearth of exposure and toxicity information available to assess potential health risks. Quantification of all trace organics in the biological fluids seems impossible and costly, regardless of the high individual exposure variability. We hypothesized that the blood concentration (CB) of organic pollutants could be predicted via their exposure and chemical properties. Developing a prediction model on the annotation of chemicals in human blood can provide new insight into the distribution and extent of exposures to a wide range of chemicals in humans. Objectives: Our objective was to develop a machine learning (ML) model to predict blood concentrations (CBs) of chemicals and prioritize chemicals of health concern. Methods: We curated the CBs of compounds mostly measured at population levels and developed an ML model for chemical CB predictions by considering chemical daily exposure (DE) and exposure pathway indicators (δij), half-lives (t1/2), and volume of distribution (Vd). Three ML models, including random forest (RF), artificial neural network (ANN) and support vector regression (SVR) were compared. The toxicity potential or prioritization of each chemical was represented as a bioanalytical equivalency (BEQ) and its percentage (BEQ%) estimated based on the predicted CB and ToxCast bioactivity data. We also retrieved the top 25 most active chemicals in each assay to further observe changes in the BEQ% after the exclusion of the drugs and endogenous substances. Results: We curated the CBs of 216 compounds primarily measured at population levels. RF outperformed the ANN and SVF models with the root mean square error (RMSE) of 1.66 and 2.07μM, the mean absolute error (MAE) values of 1.28 and 1.56μM, the mean absolute percentage error (MAPE) of 0.29 and 0.23, and R2 of 0.80 and 0.72 across test and testing sets. Subsequently, the human CBs of 7,858 ToxCast chemicals were successfully predicted, ranging from 1.29×10−6 to 1.79×10−2 μM. The predicted CBs were then combined with ToxCast in vitro bioassays to prioritize the ToxCast chemicals across 12 in vitro assays with important toxicological end points. It is interesting that we found the most active compounds to be food additives and pesticides rather than widely monitored environmental pollutants. Discussion: We have shown that the accurate prediction of "internal exposure" from "external exposure" is possible, and this result can be quite useful in the risk prioritization. https://doi.org/10.1289/EHP11305
Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases
Authors: Paulina Núñez, Rodrigo Quera, Andres J. Yarur
Journal: Drugs (2023)

In recent years, better knowledge of the pathophysiology of inflammatory bowel diseases (IBD) has led to a relevant expansion of the therapeutic arsenal for these conditions. Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. Tofacitinib, a non-selective small molecule JAK inhibitor, and upadacitinib and filgotinib, which are selective JAK-1 inhibitors, have been approved by the US Food and Drug Administration (FDA) for moderate-to-severe active ulcerative colitis. Compared to biological drugs, JAK inhibitors have a short half-life, rapid onset of action, and no immunogenicity. Both clinical trials and real-world evidence support the use of JAK inhibitors in the treatment of IBD. However, these therapies have been linked with multiple adverse events (AEs) including infection, hypercholesterolemia, venous thromboembolism, major adverse cardiovascular events, and malignancy. While early studies recognized several potential AEs, post-marketing trials have shown that tofacitinib may increase the risk of thromboembolic diseases and major cardiovascular events. The latter are seen in patients aged 50 years or older with cardiovascular risk factors. Hence, the benefits of treatment and risk stratification need to be considered when positioning tofacitinib. Novel JAK inhibitors with a more selective effect on JAK-1 have proven to be effective in both Crohn’s disease and ulcerative colitis, offering a potentially safer and efficacious therapeutic option to patients, including those with previous non-response to other therapies such as biologics. Nevertheless, long-term effectiveness and safety data are required.
Comparison of risk of complication between neuraxial anaesthesia and general anaesthesia for hip fracture surgery: a systematic review and meta-analysis
Authors: Xi Chen, Hairui Li, Songlin Li, Yiou Wang, Ruichen Ma, Wenwei Qian, Gang Chen, Jian Li
Journal: International Journal of Surgery (2023)

Controversy remains over the choice of anaesthetic technique for patients undergoing surgery for hip fracture.
Diagnostic Accuracy of Portable, Handheld Point-of-Care Tests vs Laboratory-Based Bilirubin Quantification in Neonates
Authors: Lauren E. H. Westenberg, Jasper V. Been, Sten P. Willemsen, Jolande Y. Vis, Andrei N. Tintu, Wichor M. Bramer, Peter H. Dijk, Eric A. P. Steegers, Irwin K. M. Reiss, Christian V. Hulzebos
Journal: JAMA Pediatrics (2023)

Quantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification.
The correlation of intraoperative oliguria with acute kidney injury after noncardiac surgery: a systematic review and meta-analysis
Authors: Zhaohua Pang, Shuang Liang, Manyu Xing, Nannan Zhou, Qulian Guo, Wangyuan Zou
Journal: International Journal of Surgery (2023)

Background: Acute kidney injury (AKI) occurs commonly after major surgery and is correlated with increased in-hospital morbidity and mortality. There is no consensus on whether intraoperative oliguria affects postoperative AKI. We conducted a meta-analysis to systematically assess the correlation of intraoperative oliguria with postoperative AKI. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched to identify reports on the relationship between intraoperative oliguria and postoperative AKI. Quality was assessed using the Newcastle–Ottawa Scale. The primary outcomes were the unadjusted and multivariate-adjusted odds ratios (ORs) for intraoperative oliguria to correlate with postoperative AKI. The secondary outcomes included intraoperative urine output in the AKI and non-AKI groups, the demand for postoperative renal replacement therapy (RRT), in-hospital mortality, and length of hospital stay in the oliguria and non-oliguria groups. Results: Nine eligible studies with 18 473 patients were included. The meta-analysis revealed that patients with intraoperative oliguria had a considerably greater risk of postoperative AKI (unadjusted OR: 2.03, 95% CI: 1.60–2.58, I 2 =63%, P &lt;0.00001; multivariate-adjusted OR: 2.00, 95% CI: 1.64–2.44, I 2 =40%, P &lt;0.00001). Further subgroup analysis did not find differences between different oliguria criteria or surgical types. Furthermore, the AKI group’s pooled intraoperative urine output was less (mean differences: −0.16, 95% CI: −0.26 to −0.07, P &lt;0.001). Intraoperative oliguria was associated with increased demand for postoperative RRT (risk ratios: 4.71, 95% CI: 2.83–7.84, P &lt;0.001) and in-hospital mortality (risk ratios: 1.83, 95% CI: 1.24–2.69, P =0.002), but not with prolonged length of hospital stay (mean differences: 0.55, 95% CI: −0.27 to 1.38, P =0.19). Conclusions: Intraoperative oliguria was significantly associated with a higher incidence of postoperative AKI, as well as increased in-hospital mortality and demand for postoperative RRT, but not with prolonged hospitalization.